The manufacture of pharmaceutical compositions comprises several aspects, one of them being the task of providing active ingredients in an appropriate form. Ideally active ingredients, especially those having an unpleasant taste, are prepared so that the patient taking a pharmaceutical composition does not refrain from doing so because of the unpleasant taste.
Taste masking is useful in the field of veterinary medicine because animals are sensitive to taste, and unlike humans, cannot be “persuaded” by reasoned argument to swallow a composition that the animal perceives as unpleasant. In most cases pharmaceutical compositions for animals include specific flavors, e.g. meat flavor for predominantly carnivorous animals. Such flavors, however, simply add to the taste of the medicine itself and serve to cover the taste perception, but in many cases adding flavor is not sufficient if the taste of the compound is still perceivable by the animal patient. On the contrary, bitter or otherwise unpleasant compounds intended for oral application in veterinary medicine are preferably hidden away, especially from the animal's perception. Such taste masking is a severe restriction for the use of pharmaceutical compositions in veterinary medicine.
In addition, the release of the active ingredient of a pharmaceutical composition to the patient's body needs to be optimized with respect to the envisaged activity of the compound. This optimization applies to oral compositions, especially those that are desired to dissolve, e.g. in the stomach, shortly after administration.
The problem of an adequate formulation of an active ingredient has to be solved for every pharmaceutical composition. It occurs for all active compounds used for all sorts of medical treatments. In particular, oral dosage forms are confronted with the need of masking a taste when the addition of flavoring agents alone is not sufficient to mask the unpleasant taste of the active compound.
In pharmaceutics while developing a solid dosage form, a taste is usually masked by applying a film coat consisting of a taste neutral polymer onto a whole tablet. But this technique does not solve the problem discussed here, especially for the treatment of predominantly carnivorous animals because a film-coated tablet is usually of neutral smell which is not attractive to the animal and therefore less likely to be ingested voluntarily. Further, many animals, especially cats, have the habit of breaking down their food by biting on it several times, and thereby, destroying the masking film and releasing the unpleasant taste. Similarly, a film-covered tablet cannot be divided in parts to optimize the individual dosage without destroying the masking film. In some cases, a tablet is not the appropriate dosage form, especially when there is a necessity for precise dose adjustment that is easier by employing a liquid dosage form. Accordingly this issue also applies to liquid pharmaceutical formulations.
Metabolic disorders like diabetes can in principle be treated by the oral application of respective pharmaceutical compositions, e.g. those that comprise DPP IV-inhibitors. Inhibitors of DPP IV belonging to the structural class of xanthine derivatives are disclosed generically by WO 02/068420 A1.
The compound 1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(R)-amino-piperidin-1-yl]-xanthine is described explicitly in WO 2005/085246 A1, example 1(52). Its mono- and di-hydrochloride, as well as, polymorphs of the free base and the hydrochlorides are described in WO 2007/014886 A1. These applications disclose methods for the chemical synthesis of this compound along with its salts, hydrates and other forms.
International patent application PCT/EP2011/054440 pertains to pharmaceutical compositions comprising the compound 1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(R)-amino-piperidin-1-yl]-xanthine in the form of the free base, as well as, every other chemical form, including solvates, prodrug esters, stereoisomers, and salts (especially the monohydrochloride) for the treatment of a metabolic disorder or metabolic disease of a predominantly carnivorous non-human animal like dog (canine) or cat (feline). Such disorders are selected from ketoacidosis, pre-diabetes, diabetes mellitus type 1 or type 2, insulin resistance, obesity, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids, hyperlipidemia and/or elevated blood levels of glycerol, Syndrome X (metabolic syndrome), atherosclerosis, inflammation of the pancreas and/or inflammation of adipose tissue, preferably ketoacidosis, pre-diabetes and/or diabetes mellitus type 1 or type 2, more preferred diabetes mellitus type 2.
This application discloses an oral application of the active ingredient. However, it does not teach a specific granulation or manufacturing technique for the active compound. An appropriate taste masking of the compound is still desirable, especially because of the bitter taste of the substance.
Other examples of active ingredients intended for an oral application are those for the treatment of heart diseases. Heart diseases include for example coronary heart diseases, cardiomyopathies, cardiovascular diseases, heart failure, hypertensive heart diseases or valvular heart diseases. These different classes of heart diseases are treated with therapies or combined therapies and hence with different classes of compounds. Therapies include administering one or more ACE inhibitors, beta-blockers, angiotensine II receptor antagonists, diuretics, Ca2+-sensitising agents, antiarrthythmic agents, cardioac glycosides or bradycardic agents such as iF-channel blockers.
European patent application EP 224794 A2 discloses a number of cyclic amine derivatives falling under a general formula including their chemical synthesis, the molecule 3-[(N-(2-(3,4-dimethoxy-phenyl)-ethyl)-piperidin-3-yl)-methyl]-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on being one of them. They are described to exert a heart frequence lowering activity in rat. Its enationamer with the chemical name (+)-3-[(N-(2-(3,4-dimethoxy-phenyl)ethyl)-piperidin-3-(5)-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on carries the international nonproprietary name (INN) cilobradine. The derived hydrochloride can be named as cilobradine hydrochloride. Cilobradine and its hydrochloride are highly water-soluble.
WO 01/78699 A2 discloses the use of structurally diverse bradycardiac substances such as calcium channel blockers, beta-receptor blockers and if-channel blockers, optionally in combination with cardio-active substances, for treating and even inducing the regression of myocardial diseases associated with hypertrophy, in particular for treating ideopathic hypertrophic cardiomyopathies (HCM) in humans and domestic animals. One of the if-channel blockers that is mentioned is cilobradine, which has a bitter taste. WO 01/78699 A2 discloses that the active ingredient, such as cilobradine, can be provided in the form of a simple mixture with other ingredients and assembled in a capsule, in the form of a granulate or a dragée, based on the same granulate, coated with a mixture of corn starch and sugar. Solutions comprising the active ingredient dissolved in a liquid are also disclosed.
Cilobradine is further disclosed to be useful for the treatment or prevention of heart failure, by EP 1362590 A1. Whereas the examples of this publication disclose the application of the active ingredient by injection, the disclosure also describes drinking solutions which are clearly easier to handle by a patient. Another use of bradycardic substances, like if-channel blockers and especially cilobradine, is disclosed by EP 1762179 A1, which discloses that these substances can be used for improving diagnostic quality in echocardiography.
Further pharmaceutically active compounds which are advantageously applied orally and confronted with the need and/or desire of masking their taste are per se known to the skilled person.
To address the problem of taste-masking an active ingredient(s) that is incorporated into pharmaceutical compositions, specific techniques have evolved in the state of the art. These are mostly coating techniques that coat, i.e. cover, the active ingredient by another substance in which the other substance serves as a physicochemical barrier against the evaporation, dissolution, or diffusion of the active ingredient. The coated particle is used as one component of the complete pharmaceutical composition. The barrier function of the protective coating should last as long as the pharmaceutical composition is stored and/or the ingredient could otherwise be perceived by the patient. Multiphase systems can be used to keep the active ingredient in a separate phase from the remainder of the composition. However, the pharmaceutical composition should dissolve or become permeable as soon as necessary for the ingredient to become active.
One technique is to prepare particles comprising the active ingredient by using a granulation step followed by a coating step. EP 292840 A2 exemplifies this technique in its example I (¶¶ 1444-1448) where the active ingredient is mixed with starch, sugar, polyvinylpyrrolidon and magnesium stearate, and the mixture is subsequently pressed and processed into granules. These granules are then mixed with another component and pressed into tablets. Such a tablet is finally described to be coated by a mixture of sugar and talc, thus resulting in a so-called dragee (example II, ¶¶ 1449-1451).
EP 409254 A1 addresses the dissolution aspect of granular particles comprising a core and a film layer coating the core. The disclosed cores comprise the active substance and a water-swelling agent; and the film layer contains at least ethylcellulose and a substance selected from ethylcellulose, HPMC (hydroxypropylmethylcellulose), MC (methylcellulose), L-HPC (low substituted hydroxypropylcellulose) and PVP (polyvinyl pyrrolidone). The specification describes that based on the taste perception by humans it was desired to reach a masking time of at least 20 s. The disclosed coatings allowed a masking time of 1 to at 57 s.
Coatings comprised of two or more coating layers, especially double layers, are also known. For example, the U.S. Pat. No. 4,874,613 teaches coating an inert inner core containing the active substance with a first layer surrounding the core comprising a biologically inert excipient or filler (clay like kaolin or water-soluble polymer), and a second layer surrounding the first layer comprising a mixture of a cationic copolymeric acrylate resin and a basic compound (like calcium carbonate, aluminium hydroxide or magnesium carbonate). Additionally, it teaches that the active ingredient can be fixed to the core by a binder material like polyvinylpyrolidone, methylcellulose, or pharmaceutically suitable gums and that the acrylate resin for the second coating layer can be chosen from methacrylate and neutral methacrylic acid ester copolymers. This patent exemplifies a mixture of kaolin clay and povidone (polyvinyl pyrrolidone) as a first layer and a mixture of calcium carbonate and Eudragit E-100 copolymeric methacrylate resin as a second layer. In both cases isopropanol and acetone are used as solvents for the preparation of the respective coating layer and allowed to evaporate after the addition of the respective material.
WO 03/075895 A1 discloses taste masked veterinary solid compositions consisting of a substrate in pellet or tablet form in which fine-grained particles of a neutral-tasting, physiologically compatible, solid carrier material are embedded. These fine-grained particles of carrier material have an average diameter of 0.09 to 0.8 mm and are coated with an active substance. This active substance layer is covered with a protective layer of a physiologically compatible polymer matrix. Thus, the active ingredient is not present in the core but in a first layer that is protected by a second layer. In such particles, the outer layer fulfills the same task and exerts the same disadvantages as those cited above where the active substance is located in the core. The distinction is that the production process is started with an inert core and that the active ingredient is applied to that core by a coating step.
A disadvantage of layering techniques is that a highly soluble compound tends to dissolve at least partially in the coating solution during the coating step, so that after drying small amounts of the substance are then distributed also in the coating layer. In some cases this might not be critical; however, unpleasant tasting substances are perceptible by an animal which will often refrain from taking the preparation.
The technique of multiple layering can be used for the manufacture of particles with more than one active ingredient. EP 2127643 A1 discloses granules, consisting of an inert core, coated with the (first) active ingredient, further coated with a release-regulating polymer, finally coated with a so-called functional ingredient. Such functional ingredient can be, for example, an inhibitor of the first active ingredient thus allowing a timely regulated activity profile of this compound. But, the release-regulating polymer is not a polymer that completely inhibits the release of the active compound but is used as a diffusion barrier leading only to time-delayed release. Such particles do not solve the problem discussed here.
European patent application EP 551820 A1 addresses the same problem especially with respect to overall liquid medical formulations. It teaches the preparation of particles that comprise an active ingredient by fluid bed granulation processes. In a second step such granules are coated by a lacquer, also called a microencapsulation process. A large number of theoretically possible coating substances, esp. polymers, is disclosed. Exemplified substances are combinations of Eudragit® NE 30 D with HPMC, with MC and with triethyl citrate. However, the essence of this development resides in the fact that the active ingredient is not used as it is, esp. not as a water soluble salt but in its least water soluble form like the free acid or the free base. Accordingly, this teaching does not extend to the respective salts or other water soluble forms of the pharmaceutically active ingredient.
The problem of finding an appropriate taste-masking technique is also addressed by WO 2006/074185 A2, which describes dissolving or dispersing a pH dependant polymer and a so called “non-plasticizing active pharmaceutical ingredient” in a solvent which is granulated by itself (and thus forming an active ingredient containing core) or used as material for forming layers over a solid support. Both approaches are then optionally followed by applying a taste masking overcoating layer. WO 2006/074185 A2 provides that the pH dependent polymer itself serves as taste masking agent, meaning that the active compound and the protective agent are not separated in two phases but form one phase. Due to the physicochemical interaction between the compound and the polymer this one phase does not dissolve but stays intact as long as the taste perception might occur. The specification explains that useful active pharmaceutical ingredients for this technique are characterized by the fact that they are relatively non-tacky and generally will remain relatively non-tacky so as to render coated solid supports workable when combined with the first taste masking material whether or not up to about 25% by weight of a conventional anti-tack agent, such as talc or magnesium stearate is added. But, a “plasticizing” active pharmaceutical ingredient cannot meet this requirement. Accordingly this teaching cannot be generally applied to all sorts of active ingredients.
The granules (or pellets) provided by all of these techniques are usually not used per se as pharmaceutical substances but represent formulation intermediates to be integrated into more complex pharmaceutical compositions. Such a composition can be e.g. in solid form (for example a tablet), or in liquid form (for example a suspension), which is another burden for the stability and/or disintegration properties of the incorporated substance containing particles.
The scientific publication of Wagner et al. (2000), entitled “Development of disintegrating multiple-unit tablets on a high-speed rotary tablet press”, in the European Journal of Pharmaceutics and Biopharmaceutics, volume 50, pages 285 to 291, describes the complex interplay between composition parameters such as polymers for coating, pellet size and pellet properties, the proportion of pellets in a mixture, and the type of filler-binders, and of machine parameters, such as production rate and type of feeder. The publication discloses Avicel PH 101 to be the most suitable filler-binder for the overall tablet, and with respect to coating elasticity and thickness, Eudragit FS 30 D is disclosed as an advantageous coating for granules. Pellets coated with Eudragit FS 30 D are taught to withstand the stress of tableting. However, they show disadvantages with respect to the disintegration process of the tablet.
To date, taste masking of pharmaceutically active ingredients which are water-soluble, especially highly water-soluble ones that also contain either at least one basic group and/or a bitter taste, is not resolved.
Due to the basic group and/or the bitter taste such compounds have to be masked away from the smell and/or taste perception of the patient. But the water soluble nature of the compound regularly leads to at least traces of the compound diffused within the particle and/or the coatings layers already during the coating process itself, i.e. before the respective coating layer has dried, just because the compound is dissolved at least partially by the solvent of the respective coating layer material during the coating process. Accordingly, whereas the main portion of the compound might be hidden away by the established coating techniques, traces of it may be perceptible. Such perception by the patient, especially animals, may result in the patent refraining from taking the medicament or composition.
For example, published application US 2005/287211 A1 discloses particles comprising a core of microcrystalline cellulose spheres coated by the three layers: a substance layer, a middle layer and an outer coating layer. Middle layers of the disclosed examples comprise povidone or hydroxypropylmethylcellulose (HPMC) as sole polymers. The disclosed outer coating layers comprise e.g. a mixture of HPMC and ethylcellulose or a poly(meth)acrylate. However, all exemplified middle layers additionally comprise a strongly water soluble ionic compound, in most cases NaH2PO4, Na2HPO4, Na2CO3 or citrate. This strongly water soluble ionic compound influences the physicochemical properties of the coatings not only during the dissolution of the particle (as addressed by the respective publication) but also during the production of the particle, which leads to perceptible amounts of the active ingredient by the patient/animal.
WO 2009/011967 A1 discloses particles that comprise a core of sucrose coated by the layers of a substance layer (a non-steroidal anti-inflammatory drug), a first protective layer comprising HPMC or a mixture of HPMC and polyethlenglycol (PEG), an optional enteric coating layer or intermediate coating layer (a methacrylate/acrylate-polymer with triethylcitrate) and an optional second protective layer comprising HPMC again (e.g. a mixture of HPMC and PEG). Additionally, one of the coating layers comprises a strongly water soluble ionic compound. Taste and taste masking are not addressed or considered in WO 2009/011967 A1.
WO 2010/007515 A2 discloses particles comprising an active substance containing core, protected by an inner layer (polymers which swell or dissolve in the GI tract, e.g. a mixture of HPMC and PEG), an intermediate layer with a specific physiological activity (a protease-inhibitor and/or absorption enhancer, embedded in PEG as a binding polymer), an outer layer (polymers which swell or dissolve in the GI tract like the ones for the inner layer), and optionally, a further outer layer with a gastro-resistant polymer (methacyrl-copolymers or cellulose acetate-phthalate). These particles are optimized, especially by the application of a protease-inhibitor and/or absorption enhancer and the selection of polymers, to resist untimely dissolution in the GI tract and to provide a programmable release of the active ingredient(s). The aspect of influencing the dissolution process and/or the activity of the drug substance by the addition of specifically acting proteins is not addressed by WO 2010/007515 A2.
WO 2008/075372 A1 discloses particles comprising a core of a starch containing sugar sphere, covered by a seal coat, then a substance layer (drug and HPMC) as a second coat and an outer layer comprising a mixture of the material Surelease® (ethylcellulose admixed with coconut oil) mixed in a ratio of 6:1 (w/w) with HPMC. But, these particles do not comprise a further protective layer. It was also found disadvantageous to store the active substance in a middle layer and not in the lowest possible layer. This structure affects the dissolution profile, as well as, the production process.
Finally, the particles of WO 2008/027993 A2 are composed of an inert core, an amorphous layer containing the drug (with a crystallization inhibiting polymer, also named solubility-enhancing polymer, and a solubility enhancing organic acid), a protective seal-coating layer (povidone) and finally a “lag-time coating” (TPR coating; water-insoluble polymer and an enteric polymer). All examples disclose outer coatings with the plasticizers diethylphthalate or triethylcitrate. So, this specific architecture aims at a sustained release following lag-time but is not optimized with respect to the production of the particle.
Accordingly, there is a need in the art to optimize the palatability of pharmaceutical compositions, especially for use in veterinary medicine by masking the taste of a pharmaceutically active compound which is water-soluble, especially a highly water-soluble active compound that also comprises either at least one basic group and/or a bitter taste. Such compositions should at the same time allow the release of the ingredient in the patient's body as soon as necessary.
Exemplary preferred pharmaceutical compositions include the pharmaceutically active ingredients of DPP IV-inhibitors, if-channel blockers, phosphodiesterase III inhibitors, cyclooxygenase 2 inhibitors, and benzodiazepine receptor agonist.
Ideally, a masking technique would allow acceptable formulation intermediates to be incorporated into oral dosage forms for pharmaceutical compositions, especially in the field of veterinary medicine in the case of an unpleasant taste of the active ingredient. Such a masking technique should be applicable to a substance containing particles that contain the active ingredient(s) in the inner core, as well as, to granules that provide the active ingredient in the form of a coating layer over an inert or already sub-coated core, the layer(s) beneath and/or the core optionally comprising other active ingredients.
A desired masking technique should be especially useful for those pharmaceutically active ingredients that are highly soluble in water and/or in other solvents that are used for coating layers. Ideally, the desired masking technique should be applicable to solid and non-solid, especially liquid, formulations with only minor variations. The dosage form should also allow subdividing into pieces or volumetric dispensing in order to adapt the dose, without destroying the taste masking of the pharmaceutically active ingredient.
Preferably, the desired masking technique is highly flexible with respect to the amount of the pharmaceutically active ingredient to be incorporated into the pharmaceutical composition; cost effective; and easy to apply in a standard manufacturing apparatus.